EVIDENCE THAT STEROID SULFATES SERVE AS BIOSYNTHETIC INTERMEDIATES: IN VIVO CONVERSION OF PREGNENOLONE-SULFATE-S35 TO DEHYDROISOANDROSTERONE SULFATE-S35.
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17-Ketosteroids↗
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THE BINDING OF ANDROSTERONE SULFATE, ETHIOCHOLANOLONE SULFATE, AND DEHYDROISOANDROSTERONE SULFATE BY HUMAN PLASMA PROTEIN.
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17-Ketosteroids↗
[Biosynthesis of keratan sulfate, chondroitin sulfate and dermatan sulfate proteoglycans].
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Chondroitin Sulfates↗
Structural features and binding properties of chondroitin sulfates, dermatan sulfate, and heparan sulfate.
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Blood Proteins↗
Sulfate could mediate the therapeutic effect of glucosamine sulfate.
Glucosamine sulfate is a controversial osteoarthritis remedy that is presumed to stimulate articular cartilage glycosaminoglycan synthesis by increasing glucosamine concentrations in the joint space. However, this is not plausible because even large oral doses of the product have no effect on serum glucosamine concentrations. We propose instead that sulfate could mediate the clinical benefit attributed to this treatment. Sulfate is required for glycosaminoglycan synthesis, and unlike glucosamine, its serum level can be modified by dietary and other factors. In this study, we tested whether oral glucosamine sulfate increases serum sulfate concentrations and whether the sulfate concentration in the synovial fluid reflects that in the serum. The serum sulfate concentration of 7 normal subjects was 331 +/- 21 micromol/L before ingestion of 1.0 g glucosamine sulfate and 375 +/- 17 micromol/L 3 hours after (P <.05). Serum sulfate concentrations decreased from 325 +/- 19 to 290 +/- 19 micromol/L when the same dose of glucosamine sulfate was ingested with 1.0 g of the analgesic drug acetaminophen, which is largely metabolized by sulfation (P <.05). Unlike glucosamine sulfate, oral sodium sulfate did not significantly increase the serum sulfate concentration. Synovial fluid and serum sulfate concentrations were closely similar when measured in 15 patients undergoing diagnostic needle aspiration of a knee effusion (r =.99, slope =.97, P <.0001). These results do not prove that glucosamine sulfate improves osteoarthritis, but considered with other data, they do provide a plausible biochemical mechanism for its reported beneficial effects. This hypothesis is clinically relevant because it predicts that nonsulfate salts of glucosamine will be ineffective and that renal function, diet, and concurrent acetaminophen therapy could confound clinical trials of this therapy.
Acetaminophen↗
Effect of low sulfate concentrations on lactate oxidation and isotope fractionation during sulfate reduction by Archaeoglobus fulgidus strain Z.
The effect of low substrate concentrations on the metabolic pathway and sulfur isotope fractionation during sulfate reduction was investigated for Archaeoglobus fulgidus strain Z. This archaeon was grown in a chemostat with sulfate concentrations between 0.3 mM and 14 mM at 80 degrees C and with lactate as the limiting substrate. During sulfate reduction, lactate was oxidized to acetate, formate, and CO2. This is the first time that the production of formate has been reported for A. fulgidus. The stoichiometry of the catabolic reaction was strongly dependent on the sulfate concentration. At concentrations of more than 300 microM, 1 mol of sulfate was reduced during the consumption of 1 mol of lactate, whereas only 0.6 mol of sulfate was consumed per mol of lactate oxidized at a sulfate concentration of 300 microM. Furthermore, at low sulfate concentrations acetate was the main carbon product, in contrast to the CO2 produced at high concentrations. We suggest different pathways for lactate oxidation by A. fulgidus at high and low sulfate concentrations. At about 300 microM sulfate both the growth yield and the isotope fractionation were limited by sulfate, whereas the sulfate reduction rate was not limited by sulfate. We suggest that the cell channels more energy for sulfate uptake at sulfate concentrations below 300 to 400 microM than it does at higher concentrations. This could explain the shift in the metabolic pathway and the reduced growth yield and isotope fractionation at low sulfate levels.
Archaeoglobus fulgidus↗
Sulfation of acetaminophen in isolated rat hepatocytes. Relationship to sulfate ion concentrations and intracellular levels of 3'-phosphoadenosine-5'-phosphosulfate.
The relationships among sulfate ion concentration, rates of acetaminophen (APAP) sulfation, and intracellular levels of the cofactor for sulfation, 3'-phosphoadenosine-5'-phosphosulfate (PAPS) were examined in isolated rat hepatocytes. APAP sulfation rates increased as the sulfate ion concentration was raised to 1.0 mM, after which further increases in sulfate ion concentration failed to influence rates of sulfation. Cellular PAPS levels were directly related to the sulfate ion concentration both in the presence and absence of APAP. However, PAPS levels were reduced by as much as 93% in the presence of APAP. At sulfate ion concentrations below 1.0 mM, the dependence of both rates of sulfation and levels of PAPS on the availability of sulfate ion indicates that rates of sulfation may be limited by the availability of PAPS when sulfate ion concentrations are in the physiological range. Because higher sulfate ion concentrations (greater than 1.0 mM) increased intracellular concentrations of PAPS without producing corresponding increases in APAP sulfation, phenol sulfotransferase activity may be rate limiting in the presence of high concentrations of sulfate ion.
Acetaminophen↗
Interactions of sulfates of divalent metals in nickel-sulfate-sensitive patients.
70 nickel-sensitive subjects who previously gave positive patch test response to 10 microliters of nickel sulfate 0.1 M, were patch tested to 10 microliters of mixed aqueous solutions containing nickel sulfate 0.1 M+magnesium sulfate 0.3 M, nickel sulfate 0.1 M+zinc sulfate, 0.3 and 0.5 M, respectively, nickel sulfate 0.1 M+ manganese sulphate 0.3 and 0.5 M, respectively nickel sulphate 0.1 M+ cadmium sulfate 0.1 and 0.3 M, respectively, nickel sulfate 0.1 M+iron sulfate (III) 0.1 and 0.3 M, respectively, and to 10 microliters of aq. cadmium sulfate 0.1 M, aq. cadmium sulfate 0.3 M, aq. iron sulfate 0.1 M, aq. iron sulfate 0.3 M. The results showed that, whilst sulfates of divalent metals with similar size and redox properties (Mg, Zn and Mn) were able to reduce or to suppress, in a dose-dependent way, the majority (75%) of nickel reactions, those with large radius and different oxidation state(Fe III), generally gave an increase in the reactions. In about 15% of the tested subjects, an increase in all the positive reactions to the mixed solutions was found. The findings seem to demonstrate that in only a majority but not all of nickel sulfate allergic reactions, is Ni(II) able to substitute for divalent ions with similar properties at the ion sites of some proteins. This tendency reproduces the results of experimental systems, in which nickel toxicity and cancerogenity are considered responsible. In contrast, in about 15% of the tested subjects, there was a general enhancement of the reactions. In these cases, either the occurrence of a "hyper-irritable" skin caused by the adopted test system or, more likely, the formation of Ni complexes with different geometries, is hypothesized.
Adult↗
Heparan sulfate-chondroitin sulfate hybrid proteoglycan of the cell surface and basement membrane of mouse mammary epithelial cells.
Chondroitin sulfate represents approximately 15% of the 35SO4-labeled glycosaminoglycans carried by the proteoglycans of the cell surface and of the basolateral secretions of normal mouse mammary epithelial cells in culture. Evidence is provided that these chondroitin sulfate-carrying proteoglycans are hybrid proteoglycans, carrying both chondroitin sulfate and heparan sulfate chains. Complete N-desulfation but limited O-desulfation, by treatment with dimethyl sulfoxide, of the proteoglycans decreased the anionic charge of the chondroitin sulfate-carrying proteoglycans to a greater extent than it decreased the charge of their constituent chondroitin sulfate chains. Partial depolymerization of the heparan sulfate residues of the proteoglycans with nitrous acid or with heparin lyase also reduced the effective molecular radius of the chondroitin sulfate-carrying proteoglycans. The effect of heparin lyase on the chondroitin sulfate-carrying proteoglycans was prevented by treating the proteoglycan fractions with dimethyl sulfoxide, while the effect of nitrous acid on the dimethyl sulfoxide-treated proteoglycans was prevented by acetylation. This occurrence of heparan sulfate-chondroitin sulfate hybrid proteoglycans suggests that the substitution of core proteins by heparan sulfate or chondroitin sulfate chains may not solely be determined by the specific routing of these proteins through distinct chondroitin sulfate and heparan sulfate synthesizing mechanisms. Moreover, regional and temporal changes in pericellular glycosaminoglycan compositions might be due to variable postsynthetic modification of a single gene product.
Animals↗
The heterogeneity of dermatan sulfate and heparan sulfate in rat liver and a shift in the glycosaminoglycan contents in carbon tetrachloride-damaged liver.
The glycosaminoglycan of rat liver can be separated into five distinct fractions; a hyaluronic acid fraction, a heparan sulfate fraction with a molar ratio of sulfate to hexosamine (S/HexN) around 0.7, a heparan sulfate fraction with a S/HexN ratio around 1.4, a dermatan sulfate fraction with a S/HexN ratio near unity, and a dermatan sulfate fraction with a S/HexN ratio around 1.3. Enzymatic analysis of the two dermatan sulfate fractions indicates that they differ significantly in that the high sulfated fraction contains relatively more N-acetylgalactosamine 4,6-bissulfate units (about 26% of the total hexosamine). In experimental injury produced by carbon tetrachloride, the low sulfated fraction increases as much as 9-fold on a dry weight basis, bearing no linear relationship to the amount of the high sulfated fraction which increases only 2-fold. A significant shift is also observed in the levels of the two heparan sulfate fractions. In this case, however, the high sulfated fraction shows a much more pronounced increase than does the low sulfated fraction. On the basis of these observations, it is suggested that for each of the dermatan sulfate and heparan sulfate classes there are at least two pools, distinguished by sulfation degree and perhaps by turnover rate and physiological function.
Animals↗
Two distinct high-affinity sulfate transporters with different inducibilities mediate uptake of sulfate in Arabidopsis roots.
Sulfate transporters present at the root surface facilitate uptake of sulfate from the environment. Here we report that uptake of sulfate at the outermost cell layers of Arabidopsis root is associated with the functions of highly and low-inducible sulfate transporters, Sultr1;1 and Sultr1;2, respectively. We have previously reported that Sultr1;1 is a high-affinity sulfate transporter expressed in root hairs, epidermal and cortical cells of Arabidopsis roots, and its expression is strongly upregulated in plants deprived of external sulfate. A novel sulfate transporter gene, Sultr1;2, identified on the BAC clone F28K19 of Arabidopsis, encoded a polypeptide of 653 amino acids that is 72.6% identical to Sultr1;1 and was able to restore sulfate uptake capacity of a yeast mutant lacking sulfate transporter genes (K(m) for sulfate = 6.9 +/- 1.0 microm). Transgenic Arabidopsis plants expressing the fusion gene construct of the Sultr1;2 promoter and green fluorescent protein (GFP) showed specific localization of GFP in the root hairs, epidermal and cortical cells of roots, and in the guard cells of leaves, suggesting that Sultr1;2 may co-localize with Sultr1;1 in the same cell layers at the root surface. Sultr1;1 mRNA was abundantly expressed under low-sulfur conditions (50-100 microm sulfate), whereas Sultr1;2 mRNA accumulated constitutively at high levels under a wide range of sulfur conditions (50-1500 microm sulfate), indicating that Sultr1;2 is less responsive to changes in sulfur conditions. Addition of selenate to the medium increased the level of Sultr1;1 mRNA in parallel with a decrease in the internal sulfate pool in roots. The level of Sultr1;2 mRNA was not influenced under these conditions. Antisense plants of Sultr1;1 showed reduced accumulation of sulfate in roots, particularly in plants treated with selenate, suggesting that the inducible transporter Sultr1;1 contributes to the uptake of sulfate under stressed conditions.
Amino Acid Sequence↗
Sulfation of sialyl N-acetyllactosamine oligosaccharides and fetuin oligosaccharides by keratan sulfate Gal-6-sulfotransferase.
We have previously cloned keratan sulfate Gal-6-sulfotransferase (KSGal6ST), which transfers sulfate from 3'-phosphoadenosine 5'-phosphosulfate to position 6 of Gal residue of keratan sulfate. In this study, we examined whether KSGal6ST could transfer sulfate to sialyl N -acetyllactosamine oligosaccharides or fetuin oligo-saccharides. KSGal6ST expressed in COS-7 cells catalyzed transfer of sulfate to NeuAcalpha2-3Galbeta1-4GlcNAc (3'SLN), NeuAcalpha2-3Galbeta1-4GlcNAcbeta1-3Galbeta1-4Gl cNAc (SL1L1), NeuAcalpha2-3Galbeta1-4(6-sulfo)GlcNAcbeta1-3(6-sulfo) Galbeta1-4(6-su lfo)GlcNAc (SL2L4), and their desialylated derivatives except for Galbeta1-4GlcNAc, but not to NeuAcalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc (SLex). When the sulfated product formed from 3'SLN was degraded with neuraminidase and reduced with NaBH(4), the resulting sulfated disaccharide alditol showed the same retention time in SAX-HPLC as that of [(3)H]Gal(6SO(4))beta1-4GlcNAc-ol. KSGal6ST also catalyzed sulfation of fetuin. When the sulfated oligosaccharides released from the sulfated fetuin after sequential digestion with proteinase and neuraminidase were subjected to a reaction sequence of hydrazin-olysis, deaminative cleavage and NaBH(4)reduction, the major product was co-eluted with [(3)H]Gal(6SO(4))beta1-4anhydromannitol in SAX-HPLC. These observations show that KSGal6ST is able to sulfate position 6 of Gal residue of 3'SLN and fetuin oligosaccharides. The relative rates of the sulfation of SL2L4 was much higher than the rate of the sulfation of keratan sulfate. These results suggest that KSGal6ST may function in the sulfation of sialyl N -acetyllactosamine oligosaccharide chains attached to glycoproteins.
Amino Sugars↗
Low-sulfated chondroitin sulfate in human blood and urine.
Blood and urinary low-sulfated chondroitin sulfate from healthy young and aged volunteers have been characterized by gel chromatography, two-dimensional electrophoresis on cellulose acetate strips and by chemical and enzymatic analysis. No difference in content of the material (24 nmol hexosamine per ml plasma) was observed regardless of age. Chemical composition (approximately 40% sulfation at 4-position of galactosamine) and molecular weight (about 8000) of blood and urinary low-sulfated chondroitin sulfates were found to be the same, though urinary excretion of the material was much higher in the aged than in the young adults (Ohkawa et al. (1972) J. Biochem. 72, 1495--1501). Low-sulfated chondroitin sulfate in serum was in a bound form with a molecular weight of more than 100000, irrespective of age. These results suggest that increase in urinary excretion of low-sulfated chondroitin sulfate in the aged is mainly due to renal dysfunction. Low-sulfated chondroitin sulfate was also the main component of acidic glycosaminoglycans in blood from patients with Hurler's syndrome who excreted excessive amounts of dermatan sulfate and heparan sulfate in urine. This suggests that low sulfated chondroitin sulfate in blood is not merely a precursor of urinary glycosaminoglycans in the case of healthy young adults.
Adult↗
Diversity and abundance of sulfate-reducing microorganisms in the sulfate and methane zones of a marine sediment, Black Sea.
The Black Sea, with its highly sulfidic water column, is the largest anoxic basin in the world. Within its sediments, the mineralization of organic matter occurs essentially through sulfate reduction and methanogenesis. In this study, the sulfate-reducing community was investigated in order to understand how these microorganisms are distributed relative to the chemical zonation: in the upper sulfate zone, at the sulfate-methane transition zone, and deeply within the methane zone. Total bacteria were quantified by real-time PCR of 16S rRNA genes whereas sulfate-reducing microorganisms (SRM) were quantified by targeting their metabolic key gene, the dissimilatory (bi)sulfite reductase (dsrA). Sulfate-reducing microorganisms were predominant in the sulfate zone but occurred also in the methane zone, relative proportion was maximal around the sulfate-methane transition, c. 30%, and equally high in the sulfate and methane zones, 5-10%. The dsrAB clone library from the sulfate-methane transition zone, showed mostly sequences affiliated with the Desulfobacteraceae. While, the dsrAB clone libraries from the upper, sulfate-rich zone and the deep, sulfate-poor zone were dominated by similar, novel deeply branching sequences which might represent Gram-positive spore-forming sulfate- and/or sulfite-reducing microorganisms. We thus hypothesize that terminal carbon mineralization in surface sediments of the Black Sea is largely due to the sulfate reduction activity of previously hidden SRM. Although these novel SRM were also abundant in sulfate-poor, methanogenic areas of the Black Sea sediment, their activities and possibly very versatile metabolic capabilities remain subject of further study.
Colony Count, Microbial↗
Difference between N-acetylgalactosamine 4-sulfate 6-O-sulfotransferases from human serum and squid cartilage in specificity toward the terminal and interior portion of chondroitin sulfate.
In the preceding paper (Inoue, H., Otsu, K., Yoneda, M., Kimata, K., Suzuki, S., and Nakanishi, Y. (1986) J. Biol. Chem. 261, 4460-4469), we reported the purification from human serum of an N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase fraction which was able to transfer sulfate predominantly to position 6 of the nonreducing terminal N-acetylgalactosamine 4-sulfate unit of chondroitin sulfate. We now show that the activity toward the terminal was co-purified with a minor activity toward the interior counterpart by sequential chromatography on heparin-Sepharose CL-6B, Matrex Blue B, hydroxyapatite, and Sephacryl S-300, and that the two activities were equally heatlabile. The enzyme purified 5000-fold from human serum was devoid of the sulfotransferase activities toward chondroitin, heparan sulfate, and keratan sulfate, but showed a strong terminal sulfotransferase activity toward dermatan sulfate (pig skin); over 97% of the sulfate residues incorporated were at position 6 of the nonreducing N-acetylgalactosamine 4,6-bissulfate end groups linked to the L-iduronic acid group. Although the enzyme introduces sulfate predominantly into the nonreducing terminal of chondroitin sulfate at physiological pH (approximately equal to 7.0) and Ca2+ concentration (approximately 2-3 mM), the activity toward the interior portion relative to that toward the terminal was increased by either lowering pH or elevating Ca2+ concentration, perhaps owing to changes in the conformation or ionic state of the acceptor molecule. Comparison between the human serum enzyme and the N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (formerly designated "E6-sulfotransferase") from squid cartilage indicated that the latter is distinct from the former in introducing sulfate predominantly into the interior portion of chondroitin sulfate. It appears that the role of the squid sulfotransferase is to synthesize so-called chondroitin sulfate E where over 50% of the interior hexosamine units are 4,6-bis-sulfated.
Animals↗
Depletion of hepatic 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and sulfate in rats by xenobiotics that are sulfated.
Sulfation is considered a high-affinity but low-capacity conjugation mechanism that is limited by the availability of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), the cosubstrate for sulfation. Salicylamide, phenol and 1-naphthol are all known substrates for the sulfation reaction. This study was conducted to determine whether the xenobiotics that are sulfated when administered to rats will lower hepatic PAPS and its precursor, sulfate. Urinary sulfate excretion was reduced 85% to 95% by these compounds. Hepatic PAPS was reduced 73%, 39%, and 87% by salicylamide, phenol and naphthol, respectively, 2 hr after administration of 2 mmol/kg. These compounds also decreased serum sulfate concentrations by 45% to 86% and lowered hepatic sulfate concentrations. In summary, these studies demonstrate that salicylamide, phenol and 1-naphthol lower hepatic PAPS and sulfate concentrations, as well as serum sulfate concentrations. These findings imply that increased sulfation, as a result of the sulfation of xenobiotics, results in depletion of hepatic PAPS concentrations, possibly because the utilization of PAPS by the sulfotransferases exceeds its generation via sulfate activation. Thus the capacity-limited sulfation of high dosages of xenobiotics appears to be due to the reduced availability of hepatic PAPS, which in turn is limited by the availability of sulfate.
Animals↗
Turnover of heparan sulfate depends on 2-O-sulfation of uronic acids.
To study how the pattern of sulfation along a heparan sulfate chain affects its turnover, we examined heparan sulfate catabolism in wild-type Chinese hamster ovary cells and mutant pgsF-17, defective in 2-O-sulfation of uronic acid residues (Bai, X., and Esko, J. D. (1996) J. Biol. Chem. 271, 17711-17717). Heparan sulfate from the mutant contains normal amounts of 6-O-sulfated glucosamine residues and iduronic acid and somewhat higher levels of N-sulfated glucosamine residues but lacks any 2-O-sulfated iduronic or glucuronic acid residues. Pulse-chase experiments showed that both mutant and wild-type cells transport newly synthesized heparan sulfate proteoglycans to the plasma membrane, where they shed into the medium or move into the cell through endocytosis. Internalization of the cell-associated molecules leads to sequential endoglycosidase (heparanase) fragmentation of the chains and eventual lysosomal degradation. In wild-type cells, the chains begin to degrade within 1 h, leading to the accumulation of intermediate (10-20-kDa) and small (4-7-kDa) oligosaccharides. Mutant cells did not generate these intermediates, although internalization and intracellular trafficking of the heparan sulfate chains appeared normal, and the chains degraded with normal kinetics. This difference was not due to defective heparanase activities in the mutant, since cytoplasmic extracts from mutant cells cleaved wild-type heparan sulfate chains in vitro. Instead, the heparan sulfate chains from the mutant were relatively resistant to degradation by cellular heparanases. These findings suggest that 2-O-sulfated iduronic acid residues in heparan sulfate are important for cleavage by endogenous heparanases but not for the overall catabolism of the chains.
Animals↗
Altered fine structures of corneal and skeletal keratan sulfate and chondroitin/dermatan sulfate in macular corneal dystrophy.
The content and fine structure of keratan and chondroitin/dermatan sulfate in normal human corneas and corneas affected by macular corneal dystrophies (MCD) types I and II were examined by fluorophore-assisted carbohydrate electrophoresis. Normal tissues (n = 11) contained 15 microg of keratan sulfate and 8 microg of chondroitin/dermatan sulfate per mg dry weight. Keratan sulfates consisted of approximately 4% unsulfated, 42% monosulfated, and 54% disulfated disaccharides with number of average chain lengths of approximately 14 disaccharides. Chondroitin/dermatan sulfates were significantly longer, approximately 40 disaccharides per chain, and consisted of approximately 64% unsulfated, 28% 4-sulfated, and 8% 6-sulfated disaccharides. The fine structural parameters were altered in all diseased tissues. Keratan sulfate chain size was reduced to 3-4 disaccharides; chain sulfation was absent in MCD type I corneas and cartilages, and sulfation of both GlcNAc and Gal was significantly reduced in MCD type II. Chondroitin/dermatan sulfate chain sizes were also decreased in all diseased corneas to approximately 15 disaccharides, and the contents of 4- and 6-sulfated disaccharides were proportionally increased. Tissue concentrations (nanomole of chains per mg dry weight) of all glycosaminoglycan types were affected in the disease types. Keratan sulfate chain concentrations were reduced by approximately 24 and approximately 75% in type I corneas and cartilages, respectively, and by approximately 50% in type II corneas. Conversely, chondroitin/dermatan sulfate chain concentrations were increased by 60-70% in types I and II corneas. Such changes imply a modified tissue content of individual proteoglycans and/or an altered efficiency of chain substitution on the core proteins. Together with the finding that hyaluronan, not normally present in healthy adult corneas, was also detected in both disease subtypes, the data support the conclusion that a wide range of keratocyte-specific proteoglycan and glycosaminoglycan remodeling processes are activated during degeneration of the stromal matrix in the macular corneal dystrophies.
Acetylglucosamine↗